The Myb locus encodes the c-Myb transcription factor, which functions as both a transcription activator and repressor. c-Myb is absolutely required for definitive hematopoiesis and has been implicated in a variety of hematopoietic tumors including leukemia and lymphoma as well as solid tumors. In a collaborative effort, we recently demonstrated that loss of a single Myb allele severely reduces colony formation in bone marrow progenitors transduced with a p210BCR/ABL producing virus and extended survival in a model of CML blast crisis. This finding has been extended to transformation of B-lineage progenitors in two models of p190BCR/ABL- dependent B-cell leukemia. Despite clear evidence for the involvement of c-Myb in mouse and avian tumors relatively little direct evidence has implicated c-Myb in human cancer until recent reports of chromosomal translocations and subtle gene amplification involving the MYB locus in several human cancers. Thus, understanding c-Myb function in human tumors and identifying the downstream mediators of c-Myb activity is crucial for understanding the relevance of c-Myb function in human cancer. Stenman and colleagues have recently identified a recurrent and tumor specific t(6;9)(q22-23;p23-24) chromosomal translocation that involves the MYB and NFIB loci in adenoid cystic carcinoma (ACC). The recurrent and unique representation of this translocation in ACC suggests that the translocation event and the resulting c-Myb/NFIB fusion protein may play a fundamental role in these tumors. We propose two aims to test the significance of the resulting c- Myb/NFIB proteins to ACC. If c-Myb/NFIB fusion protein(s) proves to be important for the maintenance or initiation of ACC, the reagents generated in this proposal will provide valuable resources to understand the biology of ACC, identify target genes that are downstream mediators of the c-Myb/NFIB fusion protein in ACC and may provide therapeutic targets. PUBLIC HEALTH RELEVANCE: The Myb locus encodes the c-Myb proto-oncogene, which functions as a transcription regulator. c-Myb is absolutely required for normal hematopoiesis and is associated with a wide variety of human leukemias, lymphomas and other malignancies such as breast and colon cancer yet little is understood about c-Myb function in human cancer. The experiments outlined in this proposal will determine if the fusion protein resultant from a recently identified consistent chromosomal translocation in Adenoid Cystic Carcinoma (ACC) that produces a c-Myb/NFIB fusion protein is important for initiation and maintenance of ACC. Completion of the proposed work will clarify the role played by c-Myb/NFIB fusion proteins in ACC and begin to identify crucial c-Myb/NFIB targets that serve as downstream mediators in ACC. These targets may prove to be potential therapeutic targets.